La ruta de señalización WNT en la determinación de progenitores pancreáticos

1 página. IX Jornadas Andaluzas Salud Investiga. Cádiz 20-22 octubre, 2010.Nuestro laboratorio trata de determinar los mecanismos moleculares implicados en la formación de los distintos tipos celulares pancreáticos adultos a partir de células progenitoras. Este conocimiento es fundamental para comprender las bases de enfermedades tan terribles como el cáncer pancreático. Además, es absolutamente necesario para el desarrollo de protocolos de formación in vitro de células beta productoras de insulina, una atractiva estrategia terapéutica para la diabetes. A este respecto, el papel de la ruta de señalización embrionaria Wnt parece ser importante ya que estudios previos han demostrado que la activación de esta ruta es necesaria para la formación de células pancreáticas a partir de células embrionarias. En nuestro proyecto nos hemos planteado determinar el efecto de la ruta Wnt sobre la formación de páncreas sobreactivando dicha ruta en progenitores pancreáticos en el ratón.Peer reviewe

Molecular Characterization of Growth Hormone-producing Tumors in the GC Rat Model of Acromegaly

D.A.C. was supported by the Nicolás Monardes program of the Andalusian Ministry of Health (C-0015-2014) and by a grant from the Andalusian Ministry of Science and Innovation (CTS-7478). A.S-M and A.L.C were supported by grants from the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación co-funded with Fondos FEDER (PI12/0143 and PI13/02043, respectively) and the Andalusian Regional Government (CTS-444) and a grant from Pfizer Spain. R.L.C. was supported by a grant from Andalusian Ministry of Health (PI0302-2012). R.M.L. was supported by grants from Proyecto de Investigación en Salud (FIS) PI13- 00651 (funded by Instituto de Salud Carlos III), CTS-1406, PI-0639-2012, BIO-0139 (funded by Junta de Andalucía) and by Ayuda Merck Serono 2013. J. P. C. was funded by a grant (BFU2013-43282-R) from Ministerio de Economía y Competitividad. CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain. J.F.M.R. is supported by the “Sara Borrell” program from the Instituto de Salud Carlos III. R.M. Luque and J.P. Castaño have received grants and lecture fees from Ipsen and Novartis. E. Venegas-Moreno and A. Soto-Moreno received grants and lecture fees from Ipsen, Novartis and Pfizer. A. Leal-Cerro received grants from Novartis and Pfizer. David Cano received a grant from Novartis

Neurocognitive Function in Acromegaly after Surgical Resection of GH-Secreting Adenoma versus Naïve Acromegaly

Patients with active untreated acromegaly show mild to moderate neurocognitive disorders that are associated to chronic exposure to growth hormone (GH) and insulin-like growth factor (IGF-I) hypersecretion. However, it is unknown whether these disorders improve after controlling GH/IGF-I hypersecretion. The aim of this study was to compare neurocognitive functions of patients who successfully underwent GH-secreting adenoma transsphenoidal surgery (cured patients) with patients with naive acromegaly. In addition, we wanted to determine the impact of different clinical and biochemical variables on neurocognitive status in patients with active disease and after long-term cure. A battery of six standardized neuropsychological tests assessed attention, memory and executive functioning. In addition, a quantitative electroencephalography with Low-Resolution Electromagnetic Tomography (LORETA) solution was performed to obtain information about the neurophysiological state of the patients. Neurocognitive data was compared to that of a healthy control group. Multiple linear regression analysis was also conducted using clinical and hormonal parameters to obtain a set of independent predictors of neurocognitive state before and after cure. Both groups of patients scored significantly poorer than the healthy controls on memory tests, especially those assessing visual and verbal recall. Patients with cured acromegaly did not obtain better cognitive measures than naïve patients. Furthermore memory deficits were associated with decreased beta activity in left medial temporal cortex in both groups of patients. Regression analysis showed longer duration of untreated acromegaly was associated with more severe neurocognitive complications, regardless of the diagnostic group, whereas GH levels at the time of assessment was related to neurocognitive outcome only in naïve patients. Longer duration of post-operative biochemical remission of acromegaly was associated with better neurocognitive state. Overall, this data suggests that the effects of chronic exposure to GH/IGF-I hypersecretion could have long-term effects on brain functions. © 2013 Martín-Rodríguez et al.Funding for this project was provided by an R&D grant from Novartis Oncology and the Plan Andaluz de Investigación (CTS-444). DAC was supported by the “Ramón y Cajal” program (RYC-2006-001071) of the Spanish Ministry of Science and Innovation.Peer Reviewe

Growth hormone as concomitant treatment in severe fibromyalgia associated with low IGF-1 serum levels. A pilot study

<p>Abstract</p> <p>Background</p> <p>There is evidence of functional growth hormone (GH) deficiency, expressed by means of low insulin-like growth factor 1 (IGF-1) serum levels, in a subset of fibromyalgia patients. The efficacy of GH versus placebo has been previously suggested in this population. We investigated the efficacy and safety of low dose GH as an adjunct to standard therapy in the treatment of severe, prolonged and well-treated fibromyalgia patients with low IGF-1 levels.</p> <p>Methods</p> <p>Twenty-four patients were enrolled in a randomized, open-label, best available care-controlled study. Patients were randomly assigned to receive either 0.0125 mg/kg/d of GH subcutaneously (titrated depending on IGF-1) added to standard therapy or standard therapy alone during one year. The number of tender points, the Fibromyalgia Impact Questionnaire (FIQ) and the EuroQol 5D (EQ-5D), including a Quality of Life visual analogic scale (EQ-VAS) were assessed at different time-points.</p> <p>Results</p> <p>At the end of the study, the GH group showed a 60% reduction in the mean number of tender points (pairs) compared to the control group (p < 0.05; 3.25 ± 0.8 <it>vs</it>. 8.25 ± 0.9). Similar improvements were observed in FIQ score (p < 0.05) and EQ-VAS scale (p < 0.001). There was a prompt response to GH administration, with most patients showing improvement within the first months in most of the outcomes. The concomitant administration of GH and standard therapy was well tolerated, and no patients discontinued the study due to adverse events.</p> <p>Conclusion</p> <p>The present findings indicate the advantage of adding a daily GH dose to the standard therapy in a subset of severe fibromyalgia patients with low IGF-1 serum levels.</p> <p>Trial Registration</p> <p>NCT00497562 (ClinicalTrials.gov).</p

Genetically Engineered Mouse Models of Pituitary Tumors

Animal models constitute valuable tools for investigating the pathogenesis of cancer as well as for preclinical testing of novel therapeutics approaches. However, the pathogenic mechanisms of pituitary-tumor formation remain poorly understood, particularly in sporadic adenomas, thus, making it a challenge to model pituitary tumors in mice. Nevertheless, genetically engineered mouse models (GEMMs) of pituitary tumors have provided important insight into pituitary tumor biology. In this paper, we review various GEMMs of pituitary tumors, highlighting their contributions and limitations, and discuss opportunities for research in the field.David A. Cano was supported by the grants from the Spanish Ministry of Science and Innovation (SAF2011-26805) and Andalusian Regional Ministry of Science and Innovation (CTS-7478). Alfonso Leal-Cerro was supported by a grant from the Spanish Ministry of Health, ISCIII (PI12/0143). Alfonso Soto-Moreno was supported by a grant from the Spanish Ministry of Health, ISCIII (PI12/02043).Peer reviewedPeer Reviewe

Rationale and design of PATRO Adults, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope(R) for the treatment of adult patients with growth hormone deficiency

PATRO Adults is an observational, multicentre, open, longitudinal, noninterventional study being conducted in hospitals and specialized endocrinology clinics across several European countries. The primary objective is to assess the safety and efficacy of Omnitrope\uae in adults treated in routine clinical practice. Eligible patients are male or female adults who are receiving treatment with Omnitrope\uae and who have provided informed consent. Patients who have been treated with another human growth hormone (hGH) product before starting Omnitrope\uae therapy will also be eligible for inclusion. Efficacy assessments will be based on the analysis of the following: insulin-like growth factor-1 levels within age- and gender-adjusted normal ranges; anthropometric measures (weight, waist circumference, total fat mass, lean body mass, total body water); bone mineral density; lipids; effects on cardiovascular risk factors such as glucose metabolism, blood pressure and inflammatory markers (e.g. C-reactive protein); and quality of life. All adverse events will be monitored and recorded. Particular emphasis will be placed on long-term safety, the recording of malignancies, the occurrence and clinical impact of antirecombinant hGH antibodies, the incidence, severity and duration of hyperglycaemia, and the development of diabetes during treatment with Omnitrope\uae

Molecular characterization of an animal model of acromegaly induced by implantation of GC somatotroph tumor cell line

Resumen del póster presentado al "8th International Congress of Neuroendocrinology" celebrado en Sydney (Australia) del 17 al 20 de agosto de 2014.-- et al.Subcutaneous implantation of GH-producing GC cells in female Wisth-Furth rats results in acromegalic phenotype (i.e. gigantism, visceromegaly, etc.). This animal model of acromegaly has been known for almost two decades and largely used to study the effects of chronic GH exposure on target tissues. However, little is known about the kinetics of tumor cell growth and information at the molecular level is scarce. In the current work Immunochemistry, molecular biology and imaging techniques were used to analyze in detail this animal model of acromegaly. GC cells (1 X 107) were injected sc into the flank of 7-week-old female rats. Control rats were injected sc with saline. Animals were weighed weekly. Tumors became palpable 2–3 weeks after implantation. For in vivo assessment of tumor growth and metabolism, microPET scans with 18F-FDG and [11C]Met were conducted at 1, 2, 4 and 8 weeks after implantation. After 20 weeks all animals were sacrificed and tumor samples were collected for further analysis. Immunohistochemical and quantitative real-time PCR analysis was conducted on tumor samples. A 1.5-2 fold increase in glucose uptake and [11C]Met accumulation was localized in the site of injection at 1 week after implantation, as compared to saline-treated rats. Highest peaks of these radiotracers at this site were found at 2 weeks after implantation. At 4 weeks, microPET scans clearly revealed evidence of tumor necrosis. Resected tumors were found to be exclusively GH-producing cells with no evidence of activation of other pituitary hormones. Analysis of somatostatin receptor expression revealed that sst2 was highly expressed followed by sst1. sst3 and sst5 were virtually absent in all samples analyzed. GHR and GHRHR were also present in the experimental tumors. Tumor cells displayed marked b-catenin and N-cadherin levels, showing a similar pattern to that found in normal pituitary, a finding consistent with the low metastastic potential of the somatotroph tumors. Interestingly, tumor cells expressed Sox2 and Sox9, two markers of pituitary progenitor cells. Altogether, our results show molecular similarities between GC-implanted tumors and human somatotroph adenomas. Thus, subcutaneous injection of GC cells might be a useful model to study the mechanisms of somatotroph adenoma tumorigenesis as well as to evaluate compounds for in vivo antitumoral activity.Peer Reviewe

GDNF is required for neural colonization of the pancreas

The mammalian pancreas is densely innervated by both the sympathetic and parasympathetic nervous systems, which control exocrine and endocrine secretion. During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.D.A.C. was supported by the Ramón y Cajal program [RYC-2006-001071] and by grants from the Spanish Ministry of Science and Innovation [SAF2008-02469 and SAF2011-26805] and the Andalusian Regional Ministry of Health [PI-0250/2008]. A.L.-C. was supported by grants from the Andalusian Regional Government [P08-CVI-3727 and CTS-444]. A.P. was supported by grants from the Spanish Ministry of Science and Innovation [SAF2009-06977] and the Andalusian Regional Government [CTS-3560]. J.L.-B. was supported by the Botín Foundation, CIBERNED, and the Spanish Ministries of Science (SAF Program) and Health.Peer Reviewe